A spontaneously hypertensive rat model of thromboembolic stroke has been developed in our laboratory that presents with parenchymal hemorrhage, hemorrhagic infarction and edema after tPA reperfusion. Autologous platelet and fibrin rich clots amenable to TtPA dissolution are used. A unique aspect of the model involves the use of in vivo imaging to rapidly screen for successful occlusions in the MCA territory, thereby reducing model variability and improving statistical power. In this proposal, we will use the model to (I) elucidate the conditions of stroke that predispose towards thrombolysis-induced hemorrhage and edema, (ii) examine the pathophysiologic mechanisms that underlie the occurrence of these complications, and (iii) test in vivo MRI methods to assess the risks of these complications. For the first aim, we will compare rates of hemorrhage and edema that result from distal vessel occlusions vs. proximal vesel occlusions. To clarify the role of hypertension we will compare our spontaneously hypertensive rat model with hybrid borderline hypertensive rates and normotensive Wistar-Kyoto rats. Additionall, hyperglycemic rats will be compared against normoglycemic rats. For the second aim we hypothesize that after thrombolytic reperfusion free radical cascades and secondary excitotoxicity damage cerebrovasculature that are already weakened by ischemia, thus leading to hemorrhage and edema. To thest this hypothesis we will antagnozie these mechanisms with the free radical scavenger (PBN, the NMDA antagonist MK801, the NO synthase inhibitor L-NA, and a novel immunoliposome to reseal vascular membrane lesions. Prevention of tPA0induced hemorrhage and/or edema will be the primary endpoint. Neuroprotection against ischemia will also be assessed as a secondary endpoint. For the third aim we will test MRI methods that measure the permeability of vascular walls. Since the likelihood of reperfusion injury is related to the degree of vascular damage, this method should have predictive value by assessing cerebrovascular integrity prior to thrombolytic therapy.